Förster Carola, Mäkela Sari, Wärri Anni, Kietz Silke, Becker David, Hultenby Kjell, Warner Margaret, Gustafsson Jan-Ake
Department of Medical Nutrition, Karolinska Institute, Novum, S-141 86 Huddinge, Sweden.
Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15578-83. doi: 10.1073/pnas.192561299. Epub 2002 Nov 18.
The mammary glands of prepubertal estrogen receptor (ER)beta-- mice are morphologically indistinguishable from those of WT littermates. It appears that, although ERbeta is expressed in the mouse mammary gland, it is not involved in ductal growth of the gland. In this study, we examined the possibility that ERbeta has a role in the differentiated function of the mammary gland. Pregnancy is rare in ERbeta-- mice, but an intensive breeding program produced seven pregnant ERbeta-- mice, of which five did not eat their offspring and continued to successful lactation. Histomorphological comparison of lactating glands revealed that alveoli were larger and there was less secretory epithelium in ERbeta-- than in WT mice. Ultrastructural analysis showed abundant milk droplets and normal apical villi in the luminal epithelial cells, but the extracellular matrix and lamina basalis were reduced, and very frequently the interepithelial cell space was increased. Levels of the adhesion molecules, E-cadherin, connexin 32, occludin, and integrin alpha2 were reduced, and no zona occludens was detectable. In addition, there was widespread expression of the proliferation marker, Ki-67, in luminal epithelial cells in ERbeta-- but not in WT mice. These findings suggest a role for ERbeta in organization and adhesion of epithelial cells and hence for differentiated tissue morphology. We speculate that, because a reduced risk for breast cancer is conferred on women who breast-feed at an early age, ERbeta could contribute to this risk reduction by facilitating terminal differentiation of the mammary gland.
青春期前雌激素受体（ER）β基因敲除小鼠的乳腺在形态上与野生型同窝小鼠的乳腺没有区别。虽然ERβ在小鼠乳腺中表达，但它似乎不参与乳腺导管的生长。在本研究中，我们探讨了ERβ在乳腺分化功能中发挥作用的可能性。ERβ基因敲除小鼠很少怀孕，但通过密集的繁殖计划产生了7只怀孕的ERβ基因敲除小鼠，其中5只没有吃掉它们的后代并持续成功泌乳。对泌乳期乳腺的组织形态学比较显示，与野生型小鼠相比，ERβ基因敲除小鼠的腺泡更大，分泌上皮更少。超微结构分析表明，管腔上皮细胞中有丰富的乳滴和正常的顶端绒毛，但细胞外基质和基底膜减少，上皮细胞间间隙经常增大。黏附分子E-钙黏蛋白、连接蛋白32、闭合蛋白和整合素α2的水平降低，未检测到紧密连接。此外，增殖标志物Ki-67在ERβ基因敲除小鼠的管腔上皮细胞中广泛表达，而在野生型小鼠中则不表达。这些发现表明ERβ在上皮细胞的组织和黏附中发挥作用，从而影响分化组织的形态。我们推测，由于早年进行母乳喂养的女性患乳腺癌的风险降低，ERβ可能通过促进乳腺的终末分化来降低这种风险。
